entecavir Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
antivirals carbocyclic nucleosides	1019	142217-69-4

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: entecavir monohydrate anhydrous entecavir BMS-200475-01 entecavir baraclude entecavir hydrate	Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase, is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases alpha, beta, and delta and mitochondrial DNA polymerase gamma with Ki values ranging from 18 to > 160 microM. Molecular weight: 277.28 Formula: C12H15N5O3 CLOGP: -2.58 LIPINSKI: 0 HAC: 8 HDO: 4 TPSA: 125.76 ALOGS: -1.63 ROTB: 2 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

entecavir monohydrate
anhydrous entecavir
BMS-200475-01
entecavir
baraclude
entecavir hydrate

Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase, is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases alpha, beta, and delta and mitochondrial DNA polymerase gamma with Ki values ranging from 18 to > 160 microM.

Molecular weight: 277.28
Formula: C12H15N5O3
CLOGP: -2.58
LIPINSKI: 0
HAC: 8
HDO: 4
TPSA: 125.76
ALOGS: -1.63
ROTB: 2

Status: OFP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

Dose	Unit	Route
0.50	mg	O

ADMET properties:

Property	Value	Reference
BDDCS (Biopharmaceutical Drug Disposition Classification System)	3	Benet LZ, Broccatelli F, Oprea TI
S (Water solubility)	2.40 mg/mL	Benet LZ, Broccatelli F, Oprea TI
EoM (Fraction excreted unchanged in urine)	70 %	Benet LZ, Broccatelli F, Oprea TI
MRTD (Maximum Recommended Therapeutic Daily Dose)	0.05 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
BA (Bioavailability)	99 %	Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H

Approvals:

Date	Agency	Company	Orphan
March 29, 2005	FDA	BRISTOL MYERS SQUIBB

FDA Adverse Event Reporting System (Female)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Hepatitis B	206.21	19.68	50	4078	3842	53341096
Hepatitis B reactivation	165.82	19.68	37	4091	1971	53342967
Drug resistance	150.59	19.68	57	4071	19905	53325033
Hepatitis B DNA increased	114.40	19.68	19	4109	201	53344737
Viral load increased	99.21	19.68	23	4105	1452	53343486
Exposure via body fluid	79.60	19.68	16	4112	512	53344426
Hepatocellular carcinoma	68.88	19.68	20	4108	3060	53341878
Hypophosphataemia	65.82	19.68	25	4103	8780	53336158
Abortion induced	54.09	19.68	23	4105	10803	53334135
Hepatic cancer	53.67	19.68	17	4111	3484	53341454
Viral mutation identified	53.25	19.68	15	4113	2059	53342879
Pathogen resistance	43.23	19.68	17	4111	6543	53338395
Osteomalacia	42.07	19.68	10	4118	703	53344235
Liver transplant	41.94	19.68	13	4115	2481	53342457
Hepatic failure	39.62	19.68	28	4100	35778	53309160
Fanconi syndrome acquired	37.93	19.68	10	4118	1071	53343867
Hepatic function abnormal	34.35	19.68	26	4102	36873	53308065
Maternal exposure during pregnancy	33.40	19.68	50	4078	155589	53189349
Hepatic encephalopathy	29.10	19.68	15	4113	10844	53334094
Pregnancy on contraceptive	27.43	19.68	8	4120	1241	53343697
Febrile neutropenia	27.34	19.68	37	4091	104899	53240039
Neutrophil count decreased	25.96	19.68	25	4103	49073	53295865
Cryoglobulinaemia	23.84	19.68	6	4122	535	53344403
Platelet count decreased	23.55	19.68	35	4093	108064	53236874
Fanconi syndrome	23.36	19.68	7	4121	1193	53343745
Abortion spontaneous	23.26	19.68	23	4105	46612	53298326
Leukopenia	22.39	19.68	28	4100	73435	53271503
Viral uveitis	21.47	19.68	4	4124	85	53344853
Gastroenteritis staphylococcal	21.42	19.68	4	4124	86	53344852
Renal impairment	21.12	19.68	29	4099	83289	53261649
Electrocardiogram P pulmonale	20.03	19.68	3	4125	15	53344923

FDA Adverse Event Reporting System (Male)

MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Hepatitis B	379.38	17.34	117	8689	6224	32498496
Drug resistance	318.92	17.34	145	8661	22820	32481900
Hepatocellular carcinoma	272.36	17.34	103	8703	10167	32494553
Hepatic cancer	264.48	17.34	92	8714	7148	32497572
Viral mutation identified	256.01	17.34	73	8733	2946	32501774
Hepatic failure	182.60	17.34	116	8690	35564	32469156
Genotype drug resistance test	182.11	17.34	29	8777	45	32504675
Hepatitis B reactivation	178.45	17.34	57	8749	3392	32501328
Hepatitis B DNA increased	177.33	17.34	39	8767	526	32504194
Pathogen resistance	119.18	17.34	56	8750	9454	32495266
Multiple-drug resistance	115.17	17.34	42	8764	3733	32500987
Osteomalacia	108.23	17.34	29	8777	924	32503796
Fanconi syndrome acquired	103.71	17.34	34	8772	2196	32502524
Viral load increased	99.65	17.34	36	8770	3114	32501606
Hepatic cirrhosis	99.45	17.34	60	8746	16749	32487971
Hepatic encephalopathy	95.50	17.34	56	8750	14839	32489881
Hypophosphataemia	95.25	17.34	47	8759	8828	32495892
Ascites	92.74	17.34	81	8725	40110	32464610
Blood HIV RNA decreased	86.58	17.34	12	8794	0	32504720
Hepatic function abnormal	72.09	17.34	74	8732	44766	32459954
Hepatitis B surface antigen positive	61.95	17.34	13	8793	138	32504582
Blood phosphorus decreased	60.21	17.34	25	8781	3141	32501579
Viral infection	52.75	17.34	40	8766	16210	32488510
Genotype drug resistance test positive	51.30	17.34	19	8787	1762	32502958
Osteoporosis	48.66	17.34	34	8772	12148	32492572
Portal vein thrombosis	40.72	17.34	20	8786	3715	32501005
Fanconi syndrome	40.19	17.34	16	8790	1804	32502916
Palmar-plantar erythrodysaesthesia syndrome	38.83	17.34	33	8773	15716	32489004
Alanine aminotransferase increased	37.25	17.34	72	8734	78407	32426313
Blood bilirubin increased	34.00	17.34	47	8759	38737	32465983
Renal impairment	32.72	17.34	75	8731	91897	32412823
Autoimmune haemolytic anaemia	32.18	17.34	18	8788	4356	32500364
Hypocalciuria	28.86	17.34	4	8802	0	32504720
Renal tubular injury	28.65	17.34	10	8796	781	32503939
Mycoplasma infection	28.05	17.34	8	8798	322	32504398
Portal vein occlusion	27.33	17.34	6	8800	80	32504640
Parotid gland haemorrhage	27.12	17.34	5	8801	25	32504695
Asymptomatic viral hepatitis	26.65	17.34	5	8801	28	32504692
Renal tubular acidosis	25.54	17.34	12	8794	2020	32502700
Retinopathy hypertensive	24.78	17.34	7	8799	272	32504448
Liver transplant	24.53	17.34	13	8793	2827	32501893
Malignant anorectal neoplasm	24.38	17.34	5	8801	47	32504673
Hepatitis B e antigen positive	23.83	17.34	5	8801	53	32504667
Aspartate aminotransferase increased	23.42	17.34	54	8752	66375	32438345
Foetal heart rate abnormal	22.73	17.34	6	8800	180	32504540
Foetal hypokinesia	21.97	17.34	7	8799	412	32504308
Blood uric acid	21.64	17.34	3	8803	0	32504720
Retinal toxicity	21.62	17.34	7	8799	434	32504286
Liver transplant rejection	21.59	17.34	11	8795	2208	32502512
Dyspnoea	21.49	17.34	41	8765	362004	32142716
Renal glycosuria	21.23	17.34	4	8802	23	32504697
Blood creatine phosphokinase increased	20.67	17.34	41	8765	45435	32459285
Antiviral drug level below therapeutic	19.57	17.34	3	8803	3	32504717
Alkalosis hypokalaemic	19.57	17.34	3	8803	3	32504717
Venoocclusive liver disease	19.32	17.34	16	8790	7349	32497371
Laryngeal erythema	18.35	17.34	3	8803	6	32504714
Jaundice	18.25	17.34	33	8773	34125	32470595
Lipase increased	18.06	17.34	17	8789	9240	32495480
Haemorrhagic cholecystitis	18.04	17.34	4	8802	56	32504664
Schistosomiasis	17.91	17.34	4	8802	58	32504662
Amylase increased	17.67	17.34	14	8792	6041	32498679
Hepatitis B antigen positive	17.49	17.34	3	8803	9	32504711

Pharmacologic Action:

Source	Code	Description
ATC	J05AF10	ANTIINFECTIVES FOR SYSTEMIC USE ANTIVIRALS FOR SYSTEMIC USE DIRECT ACTING ANTIVIRALS Nucleoside and nucleotide reverse transcriptase inhibitors
MeSH PA	D000890	Anti-Infective Agents
MeSH PA	D000998	Antiviral Agents
CHEBI has role	CHEBI:36044	anti-virus drug
CHEBI has role	CHEBI:59897	RNA-dependent DNA polymerase inhibitors

Drug Use (View source of the data)

Disease	Relation	SNOMED_ID	DOID
Chronic type B viral hepatitis	indication	61977001
Lamivudine-Refractory Chronic Hepatitis B	indication
Lactic acidosis	contraindication	91273001	DOID:3650
Liver function tests abnormal	contraindication	166603001
Steatosis of liver	contraindication	197321007
Impaired renal function disorder	contraindication	197663003
Drug Resistance to Anti-retroviral Therapy	contraindication

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	9.56	acidic
pKa2	12.33	acidic
pKa3	13.37	acidic
pKa4	4.58	Basic
pKa5	3.37	Basic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

Target	Class	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
Protein P	Polyprotein	Q9IF40_HBV	INHIBITOR			CHEMBL	CHEMBL
Protein P	Polyprotein	DPOL_HBVB1				WOMBAT-PK
Capsid protein	Unclassified	Q03732_HBV		EC50	9.62	CHEMBL

External reference:

ID	Source
4024911	VUID
N0000171606	NUI
D04008	KEGG_DRUG
4024911	VANDF
C0971023	UMLSCUI
CHEBI:473990	CHEBI
CHEMBL713	ChEMBL_ID
DB00442	DRUGBANK_ID
C413685	MESH_SUPPLEMENTAL_RECORD_UI
135398508	PUBCHEM_CID
209216-23-9	SECONDARY_CAS_RN
5968Y6H45M	UNII
1546027	RXNORM
19722	MMSL
228280	MMSL
67562	MMSL
d05525	MMSL
010730	NDDF
416248007	SNOMEDCT_US
416644000	SNOMEDCT_US
725853008	SNOMEDCT_US

Pharmaceutical products:

Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
BARACLUDE	HUMAN PRESCRIPTION DRUG LABEL	1	0003-1611	TABLET, FILM COATED	0.50 mg	ORAL	NDA	28 sections
BARACLUDE	HUMAN PRESCRIPTION DRUG LABEL	1	0003-1612	TABLET, FILM COATED	1 mg	ORAL	NDA	28 sections
BARACLUDE	HUMAN PRESCRIPTION DRUG LABEL	1	0003-1614	SOLUTION	0.05 mg	ORAL	NDA	28 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	10135-615	TABLET, FILM COATED	0.50 mg	ORAL	ANDA	29 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	10135-616	TABLET, FILM COATED	1 mg	ORAL	ANDA	29 sections
ENTECAVIR	HUMAN PRESCRIPTION DRUG LABEL	1	16714-717	TABLET, FILM COATED	0.50 mg	ORAL	ANDA	27 sections
ENTECAVIR	HUMAN PRESCRIPTION DRUG LABEL	1	16714-718	TABLET, FILM COATED	1 mg	ORAL	ANDA	27 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	16729-388	TABLET, FILM COATED	0.50 mg	ORAL	ANDA	29 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	16729-389	TABLET, FILM COATED	1 mg	ORAL	ANDA	29 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	42291-261	TABLET, FILM COATED	0.50 mg	ORAL	ANDA	28 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	42291-262	TABLET, FILM COATED	1 mg	ORAL	ANDA	28 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	42806-658	TABLET	0.50 mg	ORAL	ANDA	28 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	42806-659	TABLET	1 mg	ORAL	ANDA	28 sections
ENTECAVIR	HUMAN PRESCRIPTION DRUG LABEL	1	50771-013	TABLET, FILM COATED	0.50 mg	ORAL	ANDA	28 sections
ENTECAVIR	HUMAN PRESCRIPTION DRUG LABEL	1	50771-014	TABLET, FILM COATED	1 mg	ORAL	ANDA	28 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	51407-064	TABLET, FILM COATED	0.50 mg	ORAL	ANDA	29 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	51407-065	TABLET, FILM COATED	1 mg	ORAL	ANDA	29 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	51991-895	TABLET	0.50 mg	ORAL	ANDA	31 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	51991-896	TABLET	1 mg	ORAL	ANDA	31 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	60050-057	TABLET	0.50 mg	ORAL	ANDA	31 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	60050-077	TABLET	1 mg	ORAL	ANDA	31 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	60687-216	TABLET	0.50 mg	ORAL	ANDA	26 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	62227-101	TABLET	0.50 mg	ORAL	ANDA	28 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	62227-102	TABLET	1 mg	ORAL	ANDA	28 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	65162-446	TABLET, FILM COATED	0.50 mg	ORAL	ANDA	26 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	65162-449	TABLET, FILM COATED	1 mg	ORAL	ANDA	26 sections
Entecavir	Human Prescription Drug Label	1	65862-841	TABLET	0.50 mg	ORAL	ANDA	26 sections
Entecavir	Human Prescription Drug Label	1	65862-842	TABLET	1 mg	ORAL	ANDA	26 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	68382-920	TABLET, FILM COATED	0.50 mg	ORAL	ANDA	24 sections
Entecavir	HUMAN PRESCRIPTION DRUG LABEL	1	68382-921	TABLET, FILM COATED	1 mg	ORAL	ANDA	24 sections